Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Study of parafunctions in patients with chronic migraine.

The purpose of this paper is to present the results of a questionnaire investigating parafunctions (particularly clenching and grinding) in patients with chronic migraine presenting sign of temporomandibular disorder. The questionnaire was elaborated by the Dental Clinic of the University of Milano and completed by 125 patients experiencing chronic migraine and attending the Neurological Institute Carlo Besta for an inpatient withdrawal protocol to treat medication overuse. Our results showed high percentages of parafunctions, which were present in 80 % of patients. We note that patient information on possible behaviours and coexisting conditions which may be involved in the mechanisms of chronic headaches, as well as education about these factors, are crucial aspects in the management of chronic headache patients. We suggest that patients suffering from chronic migraine with medication overuse headache should be evaluated in relation to the possible presence of parafunctions, and as far as the need for interocclusal devices, in order to limit the role of temporomandibular dysfunctions as trigger factors or coexisting conditions favouring the development/maintaining of headache chronification.

The licensure exam in nursing degree courses: a survey in the four universities of the Lazio Region.

BACKGROUND: In recent years, the nursing licensure exam is at the centre of a national and international wide debate. This debate regards the planning of the nursing licensure exam in many Universities and the competences that this exam must certify to ensure quality, effectiveness, and ethics of nursing care from newly-graduated nurses to general public. The aim of this study was to describe the practical tests used for the licensure exam in the four Universities of the Lazio Region. The researchers analyzed the type of practical tests used and the field of competences assessed according to the degrees of performance defined by the Dublin Descriptors. METHODS: The data were collected through semi-structured interviews to Presidents, Directors and Lecturers of nursing degree courses and through direct retrieval of the written texts of the licensure exam. Two researchers analyzed the practical tests. A special lecture-grid divided into three different sections to interpret the data was created. Statistical analysis was carried out by means of Epi-info 3.5.1/2008. RESULTS: Analysis of data showed that the most used tests were Discussion of theoretical and practical aspects in context (33.6%), followed by the Test with open and/or closed questions (23,9%). Psychomotor and relational skills tests were little used. The most valued field of competence was the cognitive one (85,5%) that assessed, above all, the storage of the concept. The ability to interpret data and solve problems was less valued. CONCLUSIONS: The study showed the high discrepancy in the types of tests used in the four Universities of the Lazio Region. Universities found it difficult to assess psychomotor and relational skills of the students. Most of the cognitive tests utilized omitted the evaluation of mastery of complex competences. Therefore, there is the necessity of a new planning of the nursing licensure exam to overcome these critical issues.

Stakeholders in nursing education: their role and involvement.

INTRODUCTION: In literature, there is evidence that all stakeholders need to be involved in the curricula building process to make sure that health professionals are "educated" to meet the stakeholders' "demands". In Italy, the involvement of stakeholders in the definition of university curricula is ratified by various regulations. AIMS: To describe the major experiences of stakeholder involvement in nursing education, identify the main stakeholders for nursing education, and the processes in which they are involved. METHODS: The search strategy included an electronic exploration of the relevant databases. The search terms were: Stakeholders, Curriculum, Nursing Education combined with Boolean operators. The references of the retrieved articles were hand searched for additional related studies. RESULTS: Most of the studies identified were from the United Kingdom, Australia, and the USA. In Italy, no relevant studies were found. The most frequently identified stakeholders were: students, clinicians, educators, nurse managers. They were mainly involved during profound changes in the curricula and the implementation of new educational approaches. DISCUSSION AND CONCLUSIONS: Stakeholders are mostly involved in countries with a private funding system for universities. Such funding systems have probably developed in the academia a greater propensity to involve stakeholders, to provide recognition of success when starting new programs, and are perceived more as marketing research. This seems contrary to the spirit of the Italian and European regulatory interventions, which instead, provide a structured commitment to consolidating and expanding the collaboration among universities, users, and the world of labor. This latter collaboration should facilitate internship activities, lifelong learning, and employability of the newly-graduated professionals.

A prospective study on the early evaluation of response to androgen receptor-targeted agents with 11C-Choline, 68Ga-PSMA, and 18F-FACBC PET in metastatic castration-resistant prostate cancer: a single-center experience.

BACKGROUND: The early identification of responsive and resistant patients to androgen receptor-targeting agents (ARTA) in metastatic castration-resistant prostate cancer (mCRPC) is not completely possible with prostate-specific antigen (PSA) assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, positron emission tomography (PET) assessment might be a promising tool. PATIENTS AND METHODS: We carried out a monocentric prospective study in patients with mCRPC treated with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, Fluorine 18 fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid - FACBC) (18F-FACBC), or Gallium-68-prostate-specific-membrane-antigen (68Ga-PSMA) PET, one scan before therapy and one 2 months later. The primary aim was to investigate the performance of three novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical progression-free survival (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809). RESULTS: Regarding the primary endpoint, at log-rank test a statistically significant correlation was found between metabolic tumor volume (MTV) (P = 0.018) and total lesion activity (TLA) (P = 0.025) percentage variation among the two scans with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA total MTV and TLA at the first scan (P = 0.001 and P = 0.025, respectively), and MTV percentage variation (P = 0.031). For OS, statistically significant correlations were found for different 68Ga-PSMA and 18F-FACBC parameters and for major maximum standardized uptake value at the first 11C-Choline PET scan. CONCLUSIONS: Our study highlighted that 11C-Choline, 68Ga-PSMA, and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS, and MTV and TLA variations with 68Ga-PSMA PET a correlation with biochemical response, which could help to assess the response to ARTA.

Positive outcome of occlusal freeway space reestablishment in patients with medication overuse due to chronic migraine.

Considering the great chapter of migraines, it is important to note the signs and symptoms caused by an alteration of the relationship of the facial musculature and the occlusal freeway space (FWS) that is the distance from maximal intercuspation to the habitual rest position (measurable in 1.4-2.5 mm). To any mandible position changing (detected by periodontal, muscle and joint proprioceptors), there is an influence on the neuromuscular system and then an alteration of the FWS. A group of 60 patients with chronic migraine (CM) underwent a withdrawal of overused medication and were subjected to electromyographic and kinesiographic evaluation. All those who presented an alteration of the FWS at rest position have been subjected to treatment with orthosis device for about 12 months. The aim of our work is to obtain and define a correct mandibular position, physiological, in agreement with the neuromuscular structures of the patient. Clinical results obtained on this pool of patients, in terms of reduction of the VAS, let us understand the importance of the inviolability of the FWS and to eliminate any type of mandibular deviation with respect to the closure trajectory induced by TENS in patients suffering from CM.

Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors.

BACKGROUND: To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT. MATERIALS AND METHODS: Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features. RESULTS: Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E). CONCLUSIONS: All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.

Implementing gnathological and neuromuscular concepts in patients with chronic migraine.

Temporomandibular disorders are among the potential comorbidities of migraine, and recent reports showed that they may have a role in promoting its progression into chronic migraine (CM). In order to clarify the possible role of neuromuscular components of the stomatognathic system in patients with CM, we studied 18 patients admitted as inpatients at our Headache Unit to undergo a withdrawal protocol for medication overuse, who underwent orthosis, after clinical and instrumental gnathological evaluation. They were subsequently evaluated after 6 months. The values of electromyographic parameters as well as of pain outcomes showed a significant decrease after orthosis. The implementation of gnathological and neuromuscular concepts can have a relevant role in the management of CM patients, in the contest of a multidisciplinary approach.

The molecular profiling of solid tumors by liquid biopsy: a position paper of the AIOM-SIAPEC-IAP-SIBioC-SIC-SIF Italian Scientific Societies.

The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts' opinions, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.

Measuring fast neutrons in Hiroshima at distances relevant to atomic-bomb survivors.

Data from the survivors of the atomic bombs serve as the major basis for risk calculations of radiation-induced cancer in humans. A controversy has existed for almost two decades, however, concerning the possibility that neutron doses in Hiroshima may have been much larger than estimated. This controversy was based on measurements of radioisotopes activated by thermal neutrons that suggested much higher fluences at larger distances than expected. For fast neutrons, which contributed almost all the neutron dose, clear measurement validation has so far proved impossible at the large distances (900 to 1,500 m) most relevant to survivor locations. Here, the first results are reported for the detection of 63Ni produced predominantly by fast neutrons (above about 1 MeV) in copper samples from Hiroshima. This breakthrough was made possible by the development of chemical extraction methods and major improvements in the sensitivity of accelerator mass spectrometry for detection of 63Ni atoms (refs 8-11). When results are compared with 63Ni activation predicted by neutron doses for Hiroshima survivors, good agreement is observed at the distances most relevant to survivor data. These findings provide, for the first time, clear measurement validation of the neutron doses to survivors in Hiroshima.

Case report of a successful multidisciplinary approach to a giant scrotal malformation.

INTRODUCTION: Congenital pelvic malformations are rare and represent a difficult therapeutic challenge. Scrotal arteriovenous malformations are quite unusual, with only a few such cases reported in the literature. Only one case of scrotal malformation? due to an arteriovenous fistula resulting in azoospermia has been described. PRESENTATION OF CASE: The two-phase strategy adopted in that case permitted complete treatment of a large-sized malformation that was served by 4 main blood confluences. DISCUSSION: Angio-CT performed using reconstructions with MIP and SSD algorithms provided more detailed data about the extension of the afferents and efferents of the arteriovenous malformation, thus enabling us to plan the endovascular treatment of the lesion. CONCLUSION: A multidisciplinary approach is mandatory to achieve good results in these cases.

The understanding of congruent and incongruent referential gaze in 17-month-old infants: an eye-tracking study comparing human and robot.

Several studies have shown that the human gaze, but not the robot gaze, has significant effects on infant social cognition and facilitate social engagement. The present study investigates early understanding of the referential nature of gaze by comparing-through the eye-tracking technique-infants' response to human and robot's gaze. Data were acquired on thirty-two 17-month-old infants, watching four video clips, where either a human or a humanoid robot performed an action on a target. The agent's gaze was either turned to the target (congruent) or opposite to it (incongruent). The results generally showed that, independent of the agent, the infants attended longer at the face area compared to the hand and target. Additionally, the effect of referential gaze on infants' attention to the target was greater when infants watched the human compared to the robot's action. These results suggest the presence, in infants, of two distinct levels of gaze-following mechanisms: one recognizing the other as a potential interactive partner, the second recognizing partner's agency. In this study, infants recognized the robot as a potential interactive partner, whereas ascribed agency more readily to the human, thus suggesting that the process of generalizability of gazing behaviour to non-humans is not immediate.

Immediate breast reconstruction with latissimus dorsi flap for patients with local recurrence of breast cancer.

BACKGROUND: Ipsilateral breast cancer recurrence (IBTR) occurs in about 7% of patients with primary invasive breast tumor. Salvage mastectomy and breast reconstruction are often discussed and latissimus dorsi (LD) flap is frequently proposed. METHODS: We retrospectively investigated 111 consecutive locally relapsing patients who underwent salvage mastectomy and immediate LD reconstruction. All included patients with IBTR previously underwent conserving surgery for BC, and received a postoperative irradiation. Primary endpoints were disease free survival and overall survival. Secondary endpoints were surgical complications and re-interventions. RESULTS: Invasive ductal cancer was the most frequent histotype (60.4%) of breast cancer reappearance. rpT1, rpT2 and rpT3 were observed respectively in 50.5%, 20,7% and 3,6% of the patients. rpTis occurred in 11,7% of cases. Positive axillary nodes were observed in 9,9% of patients at reappearance. Post-operative complication other than seroma occurred in 17,1% of patients, while seroma at the donor site was observed in 61.3% of cases. At 5-year after surgery overall survival was 92% (95% CI: 85%-96%) and disease free survival was 78% (95% CI: 69%-85%). CONCLUSIONS: Immediate latissimus dorsi flap reconstruction in selected patients with isolated breast tumor recurrence, which occurred after breast irradiation, provides an effective treatment with a satisfactory outcome.